Vepdegestrant Approved for ESR1-Mutated, ER-Positive, HER2-Negative Advanced or Metastatic Breast Cancer
Expert Perspectives
By Lyn Brook
Published
The FDA approved vepdegestrant (Veppanu, Arvinas Operations), a heterobifunctional protein degrader, for adults with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative, ESR1-mutated advanced or metastatic breast cancer, as identified by an FDA-authorized test, whose disease has progressed following at least one line of endocrine therapy. In addition, the FDA approved the Guardant360 CDx as a companion diagnostic to help identify patients with breast cancer harboring ESR1 mutations who may be candidates for vepdegestrant treatment.
Why This Approval Matters
Acquired ESR1 mutations are a recognized mechanism of endocrine resistance in ER-positive, HER2-negative metastatic breast cancer, particularly after prior exposure to aromatase inhibitors and CDK4/6 inhibitors. Once resistance emerges, treatment options that maintain endocrine sensitivity become more limited. Vepdegestrant introduces an oral estrogen receptor–targeting strategy for patients with ESR1-mutated disease and demonstrated improved progression-free survival compared with fulvestrant in this biomarker-defined population. This approval further underscores the importance of molecular testing, including circulating tumor DNA–based assessment, in guiding treatment selection in metastatic breast cancer.
Breaking Down VERITAC-2
Efficacy was evaluated in VERITAC-2 (NCT05654623), a phase 3, open-label, active-controlled, multicenter trial that randomized 624 adults with ER-positive, HER2-negative, advanced or metastatic breast cancer, including 270 patients whose tumors carried ESR1 mutations. Eligible patients had disease progression after one to two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor.
Patients were randomized 1:1 to receive either:
Vepdegestrant, orally, once daily
Fulvestrant intramuscularly on Days 1 and 15 of Cycle 1 and then once monthly thereafter
Randomization was stratified by ESR1 mutation status and presence of visceral metastases. ESR1 mutation status was determined using circulating tumor DNA from blood by central or local testing.
The major efficacy end point was progression-free survival (PFS) by blinded independent central review in both the ESR1-mutated population and the overall study population. Additional efficacy end points included overall survival (OS) and objective response rate (ORR).
Among patients with ESR1-mutated tumors, vepdegestrant demonstrated a statistically significant improvement in PFS compared with fulvestrant:
Median PFS: 5.0 months with vepdegestrant versus 2.1 months with fulvestrant
Hazard ratio: 0.57
ORR: 19% with vepdegestrant versus 4% with fulvestrant
At the time of the PFS analysis, overall survival data were immature, with deaths reported in 16% of patients in the ESR1-mutated subgroup.
Managing Adverse Events
The prescribing information for vepdegestrant includes warnings and precautions for:
QTc interval prolongation
Embryo-fetal toxicity
Dosing and Administration
The recommended dose of vepdegestrant is 200 mg orally once daily with food until disease progression or unacceptable toxicity.
Resources
Clinicaltrials.gov (2026). A study to learn about a new medicine called vepdegestrant (ARV-471, PF-07850327) in people who have advanced metastatic breast cancer (VERITAC-2). NLM identifier: NCT05654623.